Studies of pathogenic Yersinia spp. over the last several decades have provided important insights into the molecular mechanisms of bacterial virulence. However, our understanding of the immunology of Yersinia infection remains relatively primitive. Previous observations demonstrate that a specific Th1 response is critical for the clearance of Yersinia infection in mice, but the role of B cells in host defense against Yersinia has not been well studied. The broad, long-term objective of our research is to use a variety of mouse models to gain a detailed understanding of host factors that are important in mediating resistance or susceptibility to Yersinia and ultimately to use this knowledge to develop immune therapies for human plague. The focus of this project is to establish a role for host B cells in Yersinia pathogenesis by analyzing immune response to Yersinia infection in wild type, B cell-deficient (BCR-/-}, and RAG-1-/- mice. We found that animals devoid of B cells exhibit enhanced early resistance to systemically administered Yersinia. However, BCR-/- mice that have survived an initial low-dose infection become only slightly more resistant than naive BCR-/- animals to re-challenge by a high dose of Yersinia. These observations suggest that B cells can inhibit innate immune response to Yersinia but they are also involved in either the generation of effector T cells, or the maintenance of memory T cells, or both. Our goals are to elucidate the molecular and cellular mechanisms by which B cells modulate both innate immunity and primary and memory T-cell response during Yersinia infection. To achieve these goals, the pattern of cytokine production by B cells in response to Yersinia and Yersinia -secreted products will be analyzed, and the role of cytokines such as IL-10, lL-6, and TGF-beta in B cell-mediated inhibition of innate immunity to Yersinia infection will be examined. In addition, BCR-/- mice that lack certain subset of T cells will be generated and analyzed to determine whether BCR-/- mice are defective in T-cell response during Yersinia infection and which subset of T-cell response is defective. lgHEL BCR-/- mice will also be generated, and these animals can produce only hen egg lysozyme-specific B cells. Analysis of Yersinia infection in lgHEL BCR-/- mice will determine whether Yersinia -nonspecific B cells can correct the defective T-cell response observed in BCR-/- mice and whether cognate antigen presentation by B cells is required for the induction of a Th2 response. Furthermore, BCR-/- and lgHEL BCR-/- mice that have survived a primary infection will be re-challenged with a high dose of Yersinia and T-cell response will be analyzed to determine whether B cells and antibodies play a role in the maintenance of memory T cells. A detailed understanding of how Yersinia infection is cleared and how immunological memory is maintained will lead to informed decision on how best to design an anti-plague therapy.